ABSTRACT This application proposes the Alcohol Drinkers' Exposure to Preventive Therapy for TB (ADEPT-TB) study, a continuation of the Uganda Alcohol Research Collaboration on HIV (ARCH) cohort of HIV-infected alcohol users in Uganda. Tuberculosis (TB) is the leading cause of mortality in persons with HIV. Isoniazid (INH) preventive therapy (IPT) decreases all-cause mortality and active TB in persons with HIV by 30-50% above and beyond the benefits of antiretroviral therapy (ART) alone. Based on these findings, the World Health Organization (WHO) recommends IPT for all persons with HIV in resource constrained settings, but warns against IPT for persons with ?regular and heavy alcohol use? due to concern for increased hepatotoxicity in heavy drinkers in settings where liver enzymes are not routinely monitored. Approximately one quarter of HIV- infected persons in sub-Saharan Africa (SSA) are heavy drinkers, but no studies have systematically assessed the safety of TB preventive therapy in alcohol users. Thus, the ADEPT-TB study aims to determine the safety and tolerability of TB preventive therapy for HIV-infected drinkers, and examine if the benefits in preventing TB outweigh the risks. Adherence to TB preventive therapy impacts the level of benefit and may also impact hepatotoxicity. Alcohol use is an established risk factor for decreased ART adherence and active TB treatment discontinuation, but it is not known whether HIV-infected drinkers on daily ART can be adherent to TB preventive therapy. Standard IPT is comprised of daily INH for 6-9 months; a shorter-course, such as 3 months of INH plus rifampicin, could improve adherence. The ADEPT-TB study will examine the safety and tolerability of, and adherence to, 6 months of daily INH (6H) and 3 months of daily INH plus rifampicin (3HR) in 380 HIV-infected drinkers in Uganda. We will randomize participants to one of the two regimens (n=190 per arm). Our first aim is to evaluate the safety and tolerability within each regimen and by level of alcohol use. Our second aim is to compare adherence by regimen; we hypothesize that adherence will be greater in the 3HR arm compared to the 6H arm. Self-reported measures of alcohol use will be augmented by phosphatidylethanol (PEth), an established biomarker of alcohol use. Objective measures of adherence will include electronic pill bottle monitoring and a novel measure of INH exposure, INH concentration in hair. We will actively monitor for hepatotoxicity using the U.S. standard of care for TB preventive therapy for heavy drinkers. We will use the safety, tolerability, and adherence results, together with the known efficacy and mortality benefit of TB preventive therapy in HIV-infected persons in SSA, and an established decision analytic model of TB preventive therapy to conduct our third aim: to determine whether the benefits of TB preventive therapy outweigh the toxicity risks for HIV-infected drinkers in resource limited settings. These data will provide critical insights to inform the guidelines for TB preventive therapy for alcohol-using, HIV-infected persons in TB endemic areas where HIV and alcohol use are common.